Method of treating diseases that respond to therapy by dopamine or dopamine agonists

ABSTRACT

The invention relates to a medicament containing (S)-2-N-propylamino-5-hydroxytetralin, the salts or prodrugs thereof. As a D3 agonist, (S)-2-N-propylamino-5-hydroxytetralin is suitable particularly for the treatment of dopa-sensitive movement disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of pending U.S. application Ser.No. 10/587,637 filed on 28 Jul. 2006, which is a national stage entryunder 35 U.S.C. §371 of International Application No. PCT/EP2004/014143,filed 13 Dec. 2004, which claims priority to German Application No. 10359 528.7, filed 18 Dec. 2003. Each of the above-referenced applicationsare incorporated herein by reference in their entirety.

BACKGROUND

Dopamine is an essential neurotransmitter of the central nervous system.The activity of dopamine is mediated via the binding to five differentdopamine receptors. These receptors can be arranged by their morphologyand their manner of signal transduction into classes “D1-like” (D1 andD5) as well as “D2-like” (D2, D3 and D4 receptors).

The D3 receptor was first cloned by Sokoloff (Nature 347, 1990, 146) andis especially expressed in the limbic system, in which emotional andcognitive processes are controlled. It is also somewhat less pronouncedin the striatal motor tissue where it serves the purpose of fineregulation of movement processes (Joyce, Pharmacol. Ther. 90, 2001,231-259). Recently the D3 receptor has been considered as a promisingtarget for the development of active agents for the treatment ofdifferent psychiatric and motor diseases.

Consequently, D3 agonists could represent valuable therapeutics for thetreatment of different types of depression, anxiety disorders, sexualdysfunctions, glaucoma, cognitive disorders, restless leg syndrome,attention deficit hyperactivity syndrome (ADHS), hyperprolactinemia,hyperprolactinoma, eating disorders, Parkinson-associated movementdisorders, dopa- and neuroleptic-induced movement disorders, e.g.,akathisia, rigor, dystonia and dyskinesia, as well as cocaine, alcohol,opiate and nicotine addiction, galactorrhea and acromegaly.

Further, D3 agonists have neuroprotective potential for the treatmentand prophylaxis of neurodegenerative disorders (Pulvirenti et al.,Trends Pharmacol. Sci. 23, 2002, 151-153; Joyce, Pharmacol. Ther. 90,2001, 231-259; EP 0 988 296; WO 03/29233; WO 93/23035).

Thus, there is a need for high affinity D3 agonists with preferablygreater functional selectivity as compared to “D1-like” receptors andwith significant selectivity as compared to the remaining “D2-like”receptors.

It was surprisingly found that (S)-2-N-propylamino-5-hydroxytetralin hasthe desired characteristics.

Racemic 2-N-propylamino-5-hydroxytetralin is known from the literature.

Hacksell et al (J. Med. Chem. 22, 1979, 1469) evaluated differentN-alkylated 2-aminotetralins in regard to their dopamine receptorstimulating activity. A particular dopaminergic activity wasdemonstrated for the racemic 2-N-propylamino-5-hydroxytetralin. However,the agonistic activity of the substance with an ED₅₀ of 40 nM/kg is onlymoderate and the AUC and the half life are short in comparison to theother evaluated compounds. It was found that aminotetralins withN,N-dialkylation were the most active and appropriate compounds for theintended oral administration.

Beaulieu et al. (Eur. J. Pharmacol. 105, 1984, 15) evaluatedN,N-disubstituted 2-aminotetralin in regard to its D2 stimulatingactivity. The racemic 2-N-propylamino-5-hydroxytetralin demonstrated amoderate activity while N,N-dialkylated 2-amino-5-hydroxy derivate, likeN-0437 (racemic rotigotine), showed a significantly higher activity.Conclusions to possible therapeutic potential of2-N-propylamino-5-hydroxytetralin were not made.

Seiler et al. (J. Med. Chem. 29, 1986, 912) disclose2-N-propylamino-5-hydroxytetralin as an educt for syntheses ofN-dialkylated compounds. A biological activity of2-N-propylamino-5-hydroxytetralin is not described.

Swart et al. (Toxicology Methods 3, 1993, 279) describe the racemate of2-N-propylamino-5-hydroxytetralin as rotigotine metabolite with weakerdopaminergic activity. Rotigotine(5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino-1-naphthalenol)is an example of a dopamine receptor agonist with D2/D3 agonisticactivity. In comparison to rotigotine, which binds with a K_(d) value of5 nM to a dopamine receptor rich membrane fraction,2-N-propylamino-5-hydroxytetralin demonstrates a clearly higher K_(d)value of 1.3 μM. The authors come to the conclusion that theN-dealkylated metabolites of rotigotine have a dopaminergic activity tooweak for them to have a therapeutic relevance.

Swart et al. (J. Analytical Toxicology 18, 1994, 71) disclose the(S)-enantiomer of 2-N-propylamino-5-hydroxytetralin as a metabolite ofrotigotine. A biological activity is not described.

Sonesson et al. (J. Med. Chem. 38, 1995, 1319) evaluated the biologicalactivity of monopropyl analogue of{[(trifluoromethyl)sulfonyl]oxy}-2-aminotetralins. The enantiomers of2-N-propylamino-5-hydroxytetralin were disclosed as intermediatesynthesis products, however they were not biologically characterized.

EP 0 026 848, EP 0 717 620, WO 94/26703 and WO 01/38321 disclose2-N-propylamino-5-hydroxytetralin as an educt for the synthesis ofN-dialkylated and sulfonated aminotetralin. The medical application of2-N-propylamino-5-hydroxytetralin is not suggested.

Van Vliet et al. (J. Med. Chem. 39, 1996, 4233) evaluate theapplicability of competition tests with D2L agonists and D2L antagonistsfor the prediction of dopamine receptor subtype selectivity. Hereaminotetralin is evaluated in regard to its D3 selectivity and potentialsuitability as antipsychotic. Within the scope of this evaluation,racemic 2-N-propylamino-5-hydroxytetralin was applied as well as 27other substances. Functional data for (ant)agonistic activity of theused substances was not collected. The medical use of2-N-propylamino-5-hydroxytetralin is not suggested. On the other hand,the authors come to the conclusion on p. 4236 that, with the exceptionof compound (+)25, none of the applied substances demonstrate thedesired pharmacological profile of a D3 selective antipsychotic.

In summary, the racemic 2-N-propylamino-5-hydroxytetralin is, from thestate of the art, known as an unselective, moderately active dopamineagonist with a modest half life. Even though a known dopaminergicactivity of the racemic 2-N-propylamino-5-hydroxytetralin has been knownsince 1969 (see Hacksell et al., supra), a medical use of this substanceis not described and is also not suggested. On the contrary, Swart etal. come to the conclusion that the N-dealkylated metabolites ofrotigotine have a dopaminergic activity which is too weak to betherapeutically relevant (Tox. Meth. 3, 1993, p. 289, last paragraph).

DETAILED DESCRIPTION

Consequently, there was no motivation for the skilled person to consideran enantiomeric separation of this obviously therapeutically unsuitablesubstance and to test the individual enantiomers for their therapeuticpotential.

It was therefore surprising that the pure (S)-enantiomer of2-N-propylamino-5-hydroxytetralin demonstrated a particular affinity toand a noticeable functional selectivity for the D3 receptor as well as apure agonistic activity, which made the substance a valuable candidatefor the treatment of diseases caused by dopamine deficiency. Thistherapeutically attractive profile of the pure (S)-enantiomer was notidentified in the previous studies with2-N-propylamino-5-hydroxytetralin.

As a matter of fact, the (S)-enantiomer of2-N-propylamino-5-hydroxytetralin in fact binds with a Ki value of 7.6nM to the D3 receptor. In comparison, the binding compared to otherdopamine receptor subtypes is considerably less pronounced. Overall thereceptor binding tests demonstrate a selectivity D3/D1 and D3/D5of >1000 and of D3/D2 of approx. 40 (Table 1).

TABLE 1 IC₅₀ value of (S)-2-N-propylamino-5- hydroxytetralin to receptorsubtypes Receptor Ki (nM) dopamine D1 (h) >10000 dopamine D2S (h) 290dopamine D3 (h) 7.6 dopamine D4.2 (h) 30 dopamine D4.4 (h) 27 dopamineD4.7 (h) 46 dopamine D5 (h) 2000

Further, it was found in functional tests that the activity of(S)-2-N-propylamino-5-hydroxytetralin is purely agonistic, and astrongly pronounced functional D3 selectivity is present in comparisonto the D1 receptor as well as a significant selectivity in comparison tothe D2 receptor (Table 2).

TABLE 2 EC₅₀ value of (S)-2-N-propylamino-5- hydroxytetralin to receptorsubtypes Receptor Subtype EC₅₀ (nM) D1 1129 D2L 2.7 D3 0.67 D4.4 23.4 D51310

In comparison to (S)-2-N-propylamino-5-hydroxytetralin the structurallyvery similar compounds AJ76 and UH232 (Hacking & Stark, ChemBioChem2002, 947) demonstrate a reduced D3 preference. Moreover, it wassurprisingly determined that (S)-2-N-propylamino-5-hydroxytetralin hasD2/D3 agonistic activity, while the structurally closely related AJ76 isdescribed as a pure antagonist. The resulting therapeutic profile of(S)-2-N-propylamino-5-hydroxytetralin differs considerably from that ofthe structurally similar AJ76.

In comparison to rotigotine, from which the(S)-2-N-propylamino-5-hydroxytetralin in minimal amounts metabolicallyemerges, (S)-2-N-propylamino-5-hydroxytetralin shows the same agonisticeffectivity (EC₅₀) to D3 receptor, but 564 times and 385 times lessaffinity to D1 and D5 receptor, respectively, and subsequently a higherselectivity for D3 in comparison to these receptors.

Consequently, an aminotetralin as high affinity D3 agonist with greatfunctional selectivity in comparison to dopaminergic D1 and D5receptors, considerable selectivity to D4.4 receptor and significantselectivity in comparison to D2L receptor is provided with(S)-2-N-propylamino-5-hydroxytetralin for the therapy of diseases whichrespond to a therapy by dopamine or dopamine agonists.

A subject matter of the present invention is thus a pharmaceuticalcomposition comprising 2-N-propylamino-5-hydroxytetralin or itspharmaceutically acceptable salts and prodrugs thereof, wherein2-N-propylamino-5-hydroxytetralin is preferred as a pure (S)-enantiomer.

In regard to the term “pure (S)-enantiomer” it is understood in thisinvention that the amount of (R)-enantiomer in the medicament ispreferred with an amount of <10 mol %, more preferably with an amount of<2 mol % and most preferred with an amount of <1 mol % in regard to thetotal amount of 2-N-propylamino-5-hydroxytetralin in the pharmaceuticalcomposition.

The term “pharmaceutically acceptable salts” encompasses in particularnon-toxic addition salts of 2-N-propylamino-5-hydroxytetralin withorganic or inorganic acids as well as their hydrates and solvates.Examples for inorganic acids comprise HCl, HBr, sulfuric acid, sulfurousacid, phosphorous acid and phosphoric acid. Organic acids compriseacetic acid, propionic acid, pyruvic acid, butyric acid, α-, β- orγ-hydroxybutyric acid, valeric acid, hydroxyvaleric acid, capronic acid,hydroxycapronic acid, caprylic acid, capric acid, lauric acid, myristicacid, palmitic acid, stearic acid, glycolic acid, lactic acid,D-glucuronic acid, L-glucuronic acid, D-galacturonic acid, glycine,benzoic acid, hydroxybenzoic acid, gallic acid, salicylic acid, vanillicacid, coumarinic acid, caffeic acid, hippuric acid, orotic acid,L-tartaric acid, D-tartaric acid, D,L-tartaric acid, meso-tartaric acid,fumaric acid, L-malic acid, D-malic acid, D,L-malic acid, oxalic acid,malonic acid, succinic acid, maleic acid, oxalic acetic acid, glutaricacid, hydroxyglutaric acid, ketoglutaric acid, adipinic acid,ketoadipinic acid, pimelic acid, glutamic acid, asparaginic acid,phthalic acid, propanetricarboxylic acid, citric acid, isocitric acid,methanesulfonic acid, toluene sulfonic acid and trifluoromethanesulfonicacid.

In this patent application the term “prodrug” of(S)-2-N-propylamino-5-hydroxytetralin describes in particular compoundsunderstood which, in the human body, particularly in plasma or duringentry through the skin or mucosa in therapeutically effective amounts,are cleaved, processed or metabolized to(S)-2-N-propylamino-5-hydroxytetralin, whereby in this patentapplication rotigotine as prodrug of 2-N-propylamino-5-hydroxytetralinis excluded.

As prodrugs, in particular derivatives of phenolic hydroxy groups, e.g.,ester, carbonates, acetals, ketals, phosphates, phosphonates, sulfates,sulfonates, carbamates and silyl ethers come into question. Especiallypreferred prodrugs are esters and carbamates.

Other prodrugs can be easily enzymically cleavable, hydrolysable orunstable derivatives of the amino function of(S)-2-N-propylamino-5-hydroxytetralin, e.g., amides, carbonates orhydroxylamines. N,N-dialkyl derivatives, as e.g. the rotigotine or(S)-2-N-propylamino-5-hydroxytetralin, are on account of their stabilitynot prodrugs in the sense of the present patent application.

The preparation of (S)-2-N-propylamino-5-hydroxytetralin can beconducted as described in the literature (see Hacksell et al., J. Med.Chem. 22, 1979, 1469; Sonesson, J. Med. Chem. 38, 1995, 1319; U.S. Pat.No. 5,442,117). The production of prodrugs via reaction of2-N-propylamino-5-hydroxytetralin with appropriate reactive precursorslike acid chlorides, acid anhydrides, carbamoyl chlorides, sulfonylchlorides, etc. is known to the skilled person in the field of clinicalchemistry. Corresponding protocols are obtainable from the relevantliterature. Examples for literature citations for the production ofprodrugs are Bundgaard: Design of Prodrugs, Elsevier, Amsterdam, 1985;Higuchi & Stella: Prodrugs as Novel Drug Delivery Systems, in AmericanChemical Society, Washington D.C., 1975; Sloan: Prodrugs—Topical andOcular Drug Delivery, Ed: M. Dekker, 1992; Roche: Design ofbiopharmaceutical properties through prodrugs and analogs, WashingtonD.C., 1977.

The basic suitability of 2-N-propylamino-5-hydroxytetralin derivative asprodrug can for example be determined by incubating the respectivecompounds under defined conditions with an enzyme cocktail, a cellhomogenizate or an enzyme-containing cell fraction and measuring theresulting 2-N-propylamino-5-hydroxytetralin. A suitable enzyme mix isfor example included in the S 9 liver preparation of the GentestCompany, Woburn, Mass., U.S.A.

Alternatively, an incubation with fresh blood or plasma or a homogenateof the dermis can follow, in order to demonstrate a liver independentmetabolism of the prodrugs as active components. For transdermalapplication an in vitro evaluation of permeation on excised skin isrequired. The final verification of the suitability and potentialactivity in the disease models is carried out by a measurement of the2-N-propylamino-5-hydroxytetralin formed from the prodrug in plasma.

In vivo a prodrug should release enough(S)-2-N-propylamino-5-hydroxytetralin that a therapeutically effectivesteady-state concentration of (S)-2-N-propylamino-5-hydroxytetralin isachieved in plasma. In general, concentrations of(S)-2-N-propylamino-5-hydroxytetralin between 0.02 and 100 ng/ml,preferably between 0.05 and 50 ng/ml and most preferably between 0.1 and40 ng/ml plasma are considered therapeutically effective concentrations.

A further embodiment of the invention is a pharmaceutical compositioncomprising a prodrug of the general formula I:

wherein R¹ is selected from the group consisting of alkyl, cycloalkyl,aryl, aralkyl, acyl, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, acetal, ketal, —C(O)NR²R³, —C(O)NHR²,—S(O)₂R², —S(O)₂OR², —P(O₂H)OR², —P(O₂H)OR², wherein R² and R³ arerespectively selected from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, benzyl orphenyl, and wherein a compound of formula I is present as a pure(S)-enantiomer.

Preferably R¹ is selected from the group of C₁₋₆ alkylcarbonyl, C₃₋₁₀cycloalkylcarbonyl, benzoyl, —C(O)NR²R³ and —C(O)NHR².

“Alkyl” can be either a branched or unbranched alkyl group whichpreferably has 1 to 10 C-atoms, more preferably 1 to 6 C-atoms and mostpreferably 1, 2 or 3 C-atoms, e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl,t-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl and n-hexyl. Alkyl groups can additionally besubstituted with one or more substituents, for example with halogen.

“Cycloalkyl” is an alkyl group which may consist only of ring-formingC-atoms or can optionally further carry branched C-atoms. Preferredchain lengths are 3-10, more preferred 4-8 or 4-6 C-atoms.

“Alkoxy” is the group —O-alkyl, wherein alkyl is preferably selectedfrom the above mentioned groups for “alkyl”. Preferred as alkoxy is aC₁₋₆ alkoxy group, more preferred is a C₁₋₃ alkoxy group.

“Aryl” is preferably phenyl. Phenyl can be, where appropriate,additionally substituted in one or more positions, e.g., with alkoxy,alkyl, halogen or nitro.

“Aralkyl” is the group -alkyl-aryl, wherein alkyl and aryl arepreferably selected from the above mentioned “alkyl” and “aryl” groupsrespectively. “Aralkyl” is preferably benzyl.

“Acyl” encompasses in particular the groups —C(O)-alkyl(“alkylcarbonyl”), —C(O)-cycloalkyl (“cycloalkylcarbonyl”), —C(O)-aryl(“arylcarbonyl”) and —C(O)-alkyl-aryl (“aralkylcarbonyl”), wherein“alkyl”, “cycloalkyl”, “aryl” and “aralkyl” are preferably selected fromthe above-mentioned groups for “alkyl”, “cycloalkyl”, “aryl” and“aralkyl”, whereby —C(O)—C₁₋₆ alkyl and —C(O)-phenyl are most preferred.Acyl is for example acetyl, propionyl, butyryl or —C(O)-phenyl(“benzoyl”).

“Alkoxycarbonyl” is the group —C(O)—O-alkyl, wherein “alkyl” ispreferably selected from the above-mentioned group “alkyl”.Alkoxycarbonyl is preferably a C₁₋₆ alkoxycarbonyl group.

“Cycloalkoxycarbonyl” is the group —C(O)—O-cycloalkyl, wherein“cycloalkyl” is preferably selected from the above-mentioned“cycloalkyl” groups.

“Aryloxycarbonyl” is the group —C(O)—O-aryl, wherein “aryl” ispreferably selected from the above-mentioned “aryl” groups.

“Aralkoxycarbonyl” is the group —C(O)—O-aralkyl, wherein “aralkyl” ispreferably selected from the above-mentioned “aralkyl” groups.

“Ketal” is in particular the group —CR′R″—O-alkyl or —CR′R″—O-aryl boundto the phenolic oxygen atom, wherein “alkyl” and “aryl” are preferablyselected from the above-mentioned groups “alkyl” and “aryl”, and whereinR′ and R″ independently represent alkyl or aryl groups. “Acetal” differsfrom “ketal” in that the substituent R′ in acetal is a hydrogen.

“Halogen” is preferably fluorine, chlorine, bromine or iodine.

A further embodiment of the invention is the use of2-N-propylamino-5-hydroxytetralin, in particular as pure (S)-enantiomer,or the salts or prodrugs thereof for the preparation of a medicament forthe treatment or prophylaxis of a disease selected from the group ofcocaine, alcohol, opiate and nicotine addiction; neurodegenerativedisorders, in particular morbus Parkinson; sexual dysfunctions, inparticular male erectile dysfunction; depression, in particularendogenous monophasic depression (“major depression”);hyperprolactinemia; hyperprolactinoma; glaucoma; cognitive disorders;restless leg syndrome; attention deficit hyperactivity syndrome (ADHS);galactorrhea; acromegaly; Parkinson-associated movement disorders, e.g.,rigor, dystonia and dyskinesia; L-dopa-induced disorders, idiopathicdystonia, in particular Segawa syndrome; neuroleptic-induced (tardive)dyskinesia, dystonia and akathisia, as well as Parkinson plus syndrome.

In this patent application, under the term “opiates” both naturallyoccurring opiates, like morphine, as well as synthetic opiates, likeheroin, are subsumed.

Further, the medicaments can be used for drug-supported ablactationafter pregnancy.

In particular the compounds according to the invention are suitable forthe manufacture of medicament for treating L-dopa-sensitive movementdisorders. Such movement disorders could be for example dyskinesia,dystonia, rigor and tremor. It is understood by the term“L-dopa-sensitive” that the movement disorder can be advantageouslyinfluenced via administration of medicaments, which influence thedopaminergic signal transduction. One typical example for this is theSegawa syndrome, an idiopathic dystonia, by which the use of L-dopa asdiagnostic criteria can be used. Other examples for L-dopa-sensitivedisorders are morbus Parkinson associated, or L-dopa orneuroleptic-induced movement disorders as well as the restless legsyndrome.

Morbus Parkinson associated or L-dopa or neuroleptic-induced movementdisorders are for example dyskinesias, dystonias and walking disorders(“freezing”). With the use of L-dopa therapy, the so-called “wearingoff” phenomenon regularly appears, which means a loss of activity ofL-dopa, which can be mitigated or slowed through the use of monotherapyor combined therapy with suitable D3 dopamine agonists.

A preferred use of (S)-2-N-propylamino-5-hydroxytetralin thus relates tothe manufacture of a medicament for the treatment of movement disorders,such as dyskinesias, dystonias and walking disorders, whichspontaneously appear in the process of Parkinson diseases, but which mayalso be induced by medication. Included in the medication-inducedmovement disorders, like dyskinesias and dystonias, are particularlythose which are induced via L-dopa or dopamine antagonists.

Finally, the pharmaceutical compositions according to the invention canalso be provided, independent from the diseases to be treated, as acombination preparation for simultaneous or sequential application.

For example, a unit to be sold which comprises a medication fortreatment of Parkinson's disease comprising L-dopa, can also encompass apharmaceutical composition which comprises(S)-2-N-propylamino-5-hydroxytetralin or pharmaceutically acceptablesalts and prodrugs thereof. In this case L-dopa and the compoundsaccording to the invention can be present in the same pharmaceuticalformulation, e.g., in a combination tablet, or also in differentapplication units, e.g., in the form of two separate tablets or in twodifferent application forms, e.g., as oral L-dopa medication and astransdermal or transmucosal (S)-2-N-propylamino-5-hydroxytetralinformulation. As according to the need, both active agents can be appliedsimultaneously or separately over time.

In a combination preparation, a sequential dose can be for exampleachieved by providing an administration form, e.g., an oral tablet,having two different layers with differing release profiles for thedifferent pharmaceutically active components. It is clear to the skilledperson that in the context of the current invention differentadministration forms and application schedules are possible, all ofwhich are subject matter of the invention.

An embodiment of the invention therefore relates to a medicament whichcomprises L-dopa or a neuroleptic agent like(S)-2-N-propylamino-5-hydroxytetralin or a pharmaceutically acceptablesalt and prodrug thereof for simultaneous or sequential application topatients.

Typically, the medicaments of the current invention consist of apharmaceutical composition which comprises, in addition to(S)-2-N-propylamino-5-hydroxtetralin or the pharmaceutically acceptablesalts and prodrugs thereof, at least one pharmaceutically acceptablecarrier or adjuvant.

The pharmaceutical formulation can be differently formulated,independently of the intended manner of application. Thus thepharmaceutical formulation can for example be adjusted for intravenous,intramuscular, intracutaneous, subcutaneous, oral, buccal, sublingual,nasal, transdermal, inhalative, rectal or intraperitoneal application.

The respective formulations and the suitable pharmaceutical carriers oradjuvants for this purpose, like fillers, disintegrants, binders,lubricants, stabilizers, flavors, anti-oxidants, preservatives,dispersants or solvents, buffers or electrolytes, are known to theperson skilled in the art in the field of pharmaceutics, and are forexample described in standard works like Sucker, Fuchs & Speiser(“Pharmazeutische Technologie”, Deutscher Apotheker Verlag, 1991) andRemington (“The Science and Practice of Pharmacy”, Lippincott, Williams& Wilkins, 2000).

In one embodiment of the invention, the pharmaceutical compositionswhich comprise the compounds according to the invention are administeredorally and can be present in the form of for example capsules, tablets,powders, granulates, coated tablets or in a liquid form.

At the same time, the formulation can be in the form of a fast releaseapplication, when a rapid onset of the effect is desired. Respectiveoral formulations are for example described in EP 0 548 356 or EP 1 126821.

Suitable formulations for fast release of(S)-2-N-propylamino-5-hydroxytetralin or pharmaceutically acceptablesalts and prodrugs thereof are in particular formulations for mucosalapplication, for example buccal or sublingual dosage forms or nasalsprays. These formulations are an ideal way to quickly counterbalancethe “lows” of L-dopa-concentration which are associated with L-dopatherapy and to treat the movement disorders associated with the“off-phases” of L-dopa therapies, e.g., akinesias.

The transmucosal formulation can be in either a solid or liquid form.Solid mucosal application forms are for example quickly disintegratingsublingual tablets or mucoadhesive application forms. Preferred areliquid formulations which are suitable for use as a spray, in particularas a nasal spray.

A mucosal formulation in spray form can be in the simplest form anactive ingredient solution. This can, if appropriate, be made isotonicwith the addition of suitable electrolytes, e.g. sodium chloride ordextrose. A transmucosal spray of (S)-2-N-propylamino-5-hydroxytetralinor a prodrug thereof can for example be an aqueous solution, a solutionin non-aqueous solvents, such as oils, glycerol or propylene glycol, oran emulsion. Further, such a transmucosal formulation can comprisebuffers usual in the pharmaceutical art to adjust the desired pH of theactive agent solution. Advantageously, the pH of a transmucosalformulation is set in a manner that the mucous membranes are notirritated during the application of the formulation. This is with nasalapplication usually the case with a mild acidic pH in the range between3 and 6. Suitable buffers are for example acetate, citrate and phosphatebuffers. Further, additional adjuvants can be present in thetransmucosal formulation, e.g., in the nasal spray, as e.g.,solubilizers, penetration improvers, preservatives, antioxidants,thickeners and additives for improvement of taste.

On the other hand, if a protracted release is desired, a formulationwith sustained release of the active agent may be used. Respective oraland non-oral formulations are likewise known from the state of the art.

For example, (S)-2-N-propylamino-5-hydroxytetralin or the salts orprodrugs thereof may be applied in the form of patches to the skin ofthe patient, wherein the active agent is preferably in a matrix ofadhesive polymer, e.g., a self-sticking polysiloxane adhesive. Examplesfor transdermal formulations are found in WO 99/49852, WO 02/89777, WO02/89778 and WO 2004/012721. Such an administration form provides foradjusting an essentially constant plasma level and therewith a constantdopaminergic stimulation during the entire interval of application (WO02/89778; Metman, Clinical Neuropharmacol. 24, 2001, 163).

On the other hand, if a medicament in the form of a subcutaneous orintramuscular depot form is desired,(S)-2-N-propylamino-5-hydroxytetralin, or the salts or prodrugs thereofcan be suspended and injected, for example, as salt crystals, e.g. ascrystalline hydrochloride, in a hydrophobic water-free medium. Anexample formulation is described in WO 02/15903.

Alternative pharmaceutical preparations can be for example infusion orinjection solutions, oils, suppositories, aerosols, sprays, patches,microcapsules or microparticles.

EXAMPLES Example 1 Determination of Receptor Affinities

The receptor affinities were measured using competition experiments. Forthis purpose the receptors are incubated with radio-labeledreceptor-specific ligands. Primarily, human receptors are used which areexpressed in cell lines. Alternatively, membrane preparations from rator bovine brains are used. The incubation conditions are published andstandardized. Differing concentrations of the substance((S)-2-N-propylamino-5-hydroxytetralin) to be tested are added to theincubation preparations, in order that a dose-binding curve can beestablished. Unspecific binding is separated from specific bindingthrough incubation with unspecific ligands. The proportion of specificbinding in different substance concentrations is represented in % of themaximum binding of the ligand. The IC₅₀ value (concentration at 50%inhibition of the binding to the ligand) and the slope are determinedwith regression analysis. Using the Cheng-Prusoff-equation, the Ki valueis determined, which then is used for comparison: the lower the Kivalue, the higher the affinity (see Table 1).

Example 2 Determination of Functional Characteristics

In order to measure the intrinsic activity of the substance, humandopamine receptors were functionally expressed in cell lines(CHO-DUKX-SRE or SH-SY5Y-SRE). That means that after binding of agonistsan intracellular signal cascade is activated, which leads to theformation of other proteins. The gene of one of these proteins,luciferase, was previously artificially introduced. Stimulation of theprotein expression additionally leads to the formation of luciferase,which in the presence of ATP induces the emission of photons (so-calledluminescence), which then can be measured photometrically. The intensityof the luminescence is proportional to the stimulation of the receptors.Dopamine agonists stimulate the luminescence while antagonists do notlead to a specific effect. However, antagonists inhibit the luminescenceinduced via either dopamine or agonist. The activity in differentsubstance concentrations is represented in % of maximal activity via theendogenous ligand or a suitable agonist. The EC₅₀ value (concentrationat 50% activation) and the slope are determined using regressionanalysis. Using the Cheng-Prusoff-equation, the Ki value is determined,which then is used for comparison: the lower the Ki value, the higherthe affinity and activity. In regard to the effect of(S)-2-N-propylamino-5-hydroxytetralin on dopamine receptors, the valuesprovided in Table 2 were found.

Example 3 In Vitro Reaction of a Prodrug into the Active Substance

From liver cell homogenates from human, primate, dog, rat or mouse, themicrosome fraction which comprises the primary metabolic enzymesrecovered by differential centrifugation; alternatively, the cytoplasmicfraction can also be recovered. The subcellular fraction is suspendedwith a buffer to obtain a solution with a defined amount of protein.After addition of 1 μM of the prodrug to be tested, an incubationfollows at 37° C. for 60 min. Subsequently,(S)-2-N-propylamino-5-hydroxytetralin is quantified using HPLC/UV orusing HPLC/MS and put into relation with the used amounts. For detailedanalysis, concentration curves or time courses are investigated.

Example 4 Depot Suspension

(a) 1411.2 g Miglyol 812 is weighed out into a Duran flask. 14.4 gImwitor 312 was added to the Miglyol and subsequently was heated for 30minutes to 80° C. while stirring. The clear solution was cooled to roomtemperature and filtered.

(b) 1188 g of the solution produced in (a) was transferred to a glasslaboratory reactor, 12 g of active agent was added and homogenized for10 minutes with an Ultraturrax at 10,000 rpm under nitrogen. Thesuspension was filled with running Ultraturrax (2,000 rpm) in brownglass flasks.

The invention claimed is:
 1. A method for treating a disease thatresponds to therapy by dopamine or a dopamine agonist in a subject inneed thereof, the method comprising administering to the subject(S)-2-N-propylamino-5-hydroxytetralin, a pharmaceutically acceptablesalt of (S)-2-N-propylamino-5-hydroxytetralin or a prodrug of(S)-2-N-propylamino-5-hydroxytetralin, wherein the prodrug correspondsin structure to the following formula:

wherein R¹ is selected from the group consisting of acyl,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, acetal, ketal,—C(O)NR²R³—C(O)NHR², —P(O₂H)OR² and —P(O₂H)R², and wherein R² and R³ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, benzyl and phenyl, wherein the disease thatresponds to therapy by dopamine or a dopamine agonist is selected fromthe group consisting of depression, an anxiety disorder, a cognitivedisorder, attention deficit hyperactivity syndrome (ADHS), restless legsyndrome, morbus Parkinson, a Parkinson-associated movement disorder,dyskinesia, dystonia, rigor and tremor.
 2. The method of claim 1,comprising administering to the subject(S)-2-N-propylamino-5-hydroxytetralin or a pharmaceutically acceptablesalt thereof.
 3. The method of claim 1, comprising administering to thesubject the prodrug of (S)-2-N-propylamino-5-hydroxytetralin, wherein R¹is selected from the group consisting of C₁₋₆ alkylcarbonyl, C₃₋₁₀cycloalkylcarbonyl, benzoyl, —C(O)NR²R³ and —C(O)NHR².
 4. The method ofclaim 1, wherein (S)-2-N-propylamino-5-hydroxytetralin, thepharmaceutically acceptable salt of(S)-2-N-propylamino-5-hydroxytetralin or the prodrug of(S)-2-N-propylamino-5-hydroxytetralin is present as a pure(S)-enantiomer.
 5. The method of claim 1, wherein(S)-2-N-propylamino-5-hydroxytetralin, the pharmaceutically acceptablesalt of (S)-2-N-propylamino-5-hydroxytetralin or the prodrug of(S)-2-N-propylamino-5-hydroxytetralin is administered in a form selectedfrom the group consisting of an infusion solution, an injectionsolution, an oily suppository, a patch, a microcapsule and amicroparticle.
 6. The method of claim 1, further comprisingadministering to the subject a further active agent.
 7. The method ofclaim 6, wherein the further active agent is L-dopa.
 8. The method ofclaim 6, wherein (S)-2-N-propylamino-5-hydroxytetralin, thepharmaceutically acceptable salt of(S)-2-N-propylamino-5-hydroxytetralin or the prodrug of(S)-2-N-propylamino-5-hydroxytetralin and the further active agent areadministered to the subject in the same or different application unitsand either together or separately.
 9. The method of claim 6, wherein(S)-2-N-propylamino-5-hydroxytetralin, the pharmaceutically acceptablesalt of (S)-2-N-propylamino-5-hydroxytetralin or the prodrug of(S)-2-N-propylamino-5-hydroxytetralin and the further active agent arepresent in the same formulation or in different formulations.
 10. Themethod of claim 1, wherein (S)-2-N-propylamino-5-hydroxytetralin, thepharmaceutically acceptable salt of(S)-2-N-propylamino-5-hydroxytetralin or the prodrug of(S)-2-N-propylamino-5-hydroxytetralin is administered to the subject inan amount to achieve a plasma concentration of(S)-2-N-propylamino-5-hydroxytetralin of between 0.02 and 100 ng/ml.